CN1149828A - Treatment of allergic rhinitis - Google Patents

Abstract

The present invention relates to the treatment of diseases caused by type I immune responses using peptide leukotriene antagonists and antihistamines.

Description

Treatment of allergic rhinitis

Scope of invention

This invention relates to the use of peptide leukotriene antagonists and antihistamines for the treatment of mammalian diseases including allergic rhinitis caused by a class I immune response.

Background of the Invention

The "Slow Responding Substance of Anaphylaxis" (SRS-A) has been shown to be a potent bronchoconstrictor released primarily by antigen-challenged mast cells and basophils. SRS-A is believed to be a major mediator in human asthma. In addition to its obvious effect on lung tissue, SRS-A can also cause changes in skin permeability and participate in acute skin allergic reactions. In addition, SRS-A has been shown to attenuate ventricular contraction and enhance the cardiovascular effects of histamine.

The discovery of naturally occurring leukotrienes and their relationship to SRS-A has fueled interest in SRS-A and other arachidonic acid metabolites. SRS-A extracted from mice, rats, guinea pigs and humans all have the characteristics of a mixture of leukotriene C ₄ (LTC ₄ ), leukotriene D ₄ (LTD ₄ ) and leukotriene E ₄ (LTE ₄ ).

Leukotrienes are eicosenoic acids produced by some arachidonic acids via the phospholipid oxygenase pathway. These ester derivatives come from LTA4, and there are two types: (1) sulfur-containing peptide side chains (LTC ₄ , LTD ₄ and LTE ₄ ), (2) non-peptide (LTB ₄ ). Leukotrienes include several natural products that play a significant role in the pathogenesis of different inflammatory and ischemic disorders. The pathophysiological role of leukotrienes has become the focus of extensive research recently.

As described by Left, AM in Biochemical Pharmacology, 35, 2, 123-127 (1986), both peptide and non-peptide leukotrienes produce microcirculatory activity that facilitates the permeation of fluids through the capillary endothelial cell membranes of most vascular beds . LTB ₄ has a strong chemotaxis and facilitates motile clearing cell aggregates and adhesion to endothelial cell membranes. LTC ₄ , LTD ₄ and LTE ₄ activate different kinds of muscles. LTC ₄ and LTD ₄ are strong bronchoconstrictors and are potent vascular smooth muscle agonists. This vasoconstriction has been shown to occur in the pulmonary, coronary, cerebral, renal and mesenteric vasculature.

Leukotrienes have been linked to many lung diseases. Leukotrienes are known to be strong bronchoconstrictors in humans. LTC ₄ and LTD ₄ have been shown to be potent and selective peripheral airway agonists more active than histamine. [See Drazen _, J.M. et al, Proc _. . [See Marom, Z. et al., Am. Rev. Respir. Dis., 126, 449-451 (1982).]

Leukotrienes have been found in nasal secretions of allergic subjects after stimulation with specific antigens in vivo. The release of leukotrienes is associated with typical allergy signs and symptoms. [See Creticos, P.S. et al., New England Journal of Medicine., 310, 25, 1626-1629 (1984).] This suggests that allergic rhinitis is another area of application for leukotriene antagonists.

The antihistamines used in the present invention are _H1 receptor antagonists. Another class of histamine receptors, designated _H2 and _H3 , have been discovered and specific antagonists of the latter two receptors have been found to have different effects than those compounds that antagonize the _H1 receptor. But the term "antihistamine" still has the meaning of _H1 receptor antagonist. For the sake of simplification, the abbreviation of antihistamine or AH as used herein means only _Hi receptor antagonist.

Histamine _H1 receptor antagonists are mainly used to reduce the symptoms of allergic reactions such as urticaria, swelling of blood vessels, rhinitis and conjunctivitis, and to control itching associated with skin disorders. Other antagonists are used to control nausea and vomiting or to treat dizziness. This work involves the treatment of symptoms associated with rhinitis, especially allergic rhinitis, with antihistamines.

As for the treatment of allergic rhinitis, antihistamines work by blocking the activity of histamine released mainly by mast cells in the early stage of allergic reaction. It can be used to control nasal itching, sneezing, runny nose and ocular symptoms such as conjunctivitis, but has no satisfactory effect on controlling nasal congestion.

It has been found that antagonism of peptide leukotrienes such as LTC ₄ , LTD ₄ and LtE ₄ together with the administration of non-sedating antihistamines provides a better approach for the treatment of rhinitis, especially allergic rhinitis and its associated symptoms.

Invention Summary

The present invention relates to a method for treating diseases caused by class I immune responses in mammals, the method comprising administering a certain amount of peptide leukotriene antagonists to subjects who are about to suffer or have suffered from the above diseases, and simultaneously administering A certain amount of antihistamines to treat the disease.

In another aspect, the present invention relates to the use of peptide leukotriene antagonists and antihistamines in the manufacture of a medicament for the treatment of diseases caused by class I immune responses. Special Instructions

The method can be used for prophylaxis and treatment of known symptoms.

The therapeutic scope includes the treatment of a class I immune response in a mammal. This type I immune response may be caused by, or may be related to, the interaction of the antigen with IgE, which results in an exacerbated antigenic response. Antigenic material from many different sources can elicit this exacerbated immune response. Examples include plant and animal material such as hair dander and pollen, or food, dust, drugs and chemicals known to cause abnormal reactions in mammals. These reactions can produce physiological changes that can lead to disease states, all of which can be treated by the methods of the present invention, including but not limited to the following symptoms: rhinitis (including allergic and chronic rhinitis), allergic dermatitis, exema , allergic conjunctivitis, urticaria, anaphylaxis and hay fever. The above only lists some diseases that can be caused by IgE/antigen interaction, and does not limit the application of the present invention in any way.

In mast cells, allergens trigger an allergic reaction shortly after binding to IgE antibodies. This induces the cells to release chemicals that produce the symptoms of allergic rhinitis. Among the released chemicals are two classes of so-called allergic mediators that can trigger symptoms, namely histamine and peptide leukotrienes. For example, for rhinitis, antihistamines can reduce sneezing, runny nose, and itchy eyes, nose, and throat. But they are not particularly effective for nasal congestion or when the allergen is present in extremely high quantities or in prolonged contact with the allergen. In allergic rhinitis with dual reactants, early histamine concentrations were associated with sneezing and itching severity, whereas late peptide leukotriene concentrations were associated with severity of nasal congestion, a symptom that can also be caused by exogenous Caused by leukotrienes given by the source.

The peptide leukotriene (PTL) antagonists (PTLA) used in the present invention are derived from compounds that modulate the activity, production or release of peptide leukotrienes, particularly _LTC4 and _LTD4 . Such compounds include compounds that can antagonize LTC ₄ and LTD ₄ receptors (i.e. receptor antagonists), or compounds that can inhibit PLT biosynthesis, for example: i.) inhibition of substrate action, such as phospholipase A ₂ ( PLA ₂ inhibitors) or CoA-independent acetyltransferases (CoA-IT inhibitors); ii.) direct inhibition of enzymes, such as 5-LO inhibitors; or iii.) inhibition of enzyme conversion/activation, such as 5-LO Activator protein (FLAP inhibitor). The invention also includes competitive inhibitors or compounds that bind irreversibly to the receptor. Of most interest are LTC ₄ and LTD ₄ receptor antagonists.

As for PTL antagonists, the present invention uses many compounds that have been used in clinical research. It is contemplated that some or all of these antagonists may find use in the treatment regimens herein. For example, it has been reported in the literature that the following compounds can be developed into receptor antagonists: Zileuton Abbott Laboratories (Abbott Laboratories); Accolate, ZD 2138 and ZD 3523 (Zeneca); MK-476 (Merck); BAYx-1005, BAYy -1015, and BAYx-7195 (Bayer); A78773 (Abbott Laboratories); AS-35 (Tanabe); DS-4574 (Diiachi); SK&F 104353, SK&F 106203 and SB 205312 (SmithKline Beecham, plc); RG 12525 Rhone-Poulenc Rorer; and CGP45715 and CGS25019C (Ciba-Geigy). These compounds and their analogs are available from various companies or can also be prepared by the chemistries described in various published patent applications and patents disclosing and claiming these compounds. This is only a brief list and is merely an example of compounds useful in the invention; it is not intended to limit the scope of the invention in any way.

PTL receptor antagonists are most preferred. The most interesting PTLA is 8-[(p-(4-phenylbutoxy)benzoyl)]amino-2-(tetrazol-5'-yl)-4-oxo-4H-1- Benzopyran and its salts, isomers, polymorphs, etc. This compound and useful analogs thereof are disclosed in US Patent 4,780,469 (issued October 25, 1988), which is incorporated herein by reference.

Any antihistamine that retains its intrinsic _H1 receptor antagonistic activity when used in combination with PLTA may be used in the present invention. Preferred AH compounds for use in the present invention are those that do not have a sedative effect but retain their effect on rhinitis symptoms. Many antihistamines have CNS depressant effects. While this feature is useful in some treatments, it is not a desirable effect in the treatment of diseases where the therapeutic goal is to remove phenomena that interfere with normally active systems. Hence the advent of so-called "non-sedating" antihistamines. This advance has been used to prepare compounds that i) have only poor ability to cross the blood-brain barrier, or ii) are more specific for peripheral histamine _H1 receptors than for CNS histamine _H1 receptors sex or stronger affinity. Examples of such compounds are: acrivastine, benzphenazole, cetirizing, loratadine, terfenadine and their carboxylic acid metabolites. Loratadine is the preferred antihistamine. These typical compounds are enumerated to give the practitioner of the invention an understanding of the characteristics of antihistamines which can be summarized by the term "non-sedating antihistamines".

Known antihistamines are available commercially or by published methods. The synthesis of antihistamines approved for use in humans has been published in the patent literature and or professional journals. Further information on antihistamines approved for use in humans can be summarized at: The Merck Index, 9th ed., Merck & Co., Rahway, NJ (1976), Cutting Handbook of Pharmacology, 6th ed., Ed. t. Z. Czacky, M.D.. Appleton Century-Crofts, New York, 1979, Chapter 49:538-550, and Goodman and Gilman, Pharmacological Basis of Therapy, 7th ed. Editors A.G. Gilman, et al., 1985 Macmillan Publishing Co., New York. All of these references also provide information on the pharmacology of these compounds and relevant research references in the field. As for specialty medicines, acrivastine is manufactured by Boroughs Wellcome. The serial number in the Chemical Abstracts System (CAS) is CAS-87848-99-5. Benfenazole is produced by Janssen, and its CAS number is CAS-68844-77-9. The hydrochloride salt of Cetirizine can be produced or obtained from Pfizer; it has two CAS numbers: CAS-83881-52-1 and CAS-83881-51-0. Loratadine, another Schering-Plough product, has the serial number CAS-79794-75-5. Terfenadine (Seldane) and its carboxylic acid metabolites are available from Marion Merrell Dow. The CAS number of terfenadine is CAS-50679-08-8. All information on these drugs can be found by searching the CAS data against the numbers given.

Since PTLA in combination with an antihistamine is more effective than either alone in treating or reducing symptoms caused by IgE/antigen interactions, it is expected that the combination product may or will contain less active ingredient than would normally be given in doses of both.

The effective amount of antihistamine is therefore lower than that without PTLA. Antihistamines are expected to be used in combination with PTLA at a minimum concentration of half the dose used alone. It is not necessary to reduce the highest dose of the concentration range, but it is also not necessary to use the highest dose currently approved for marketing antihistamines alone. For convenience, use the doses approved by the regulatory agency or agency that oversees the sale of antihistamines. For example, loratadine is approved for sale in some countries as a tablet containing 10 mg (u.i.d.). Terfenadine is approved for sale in tablets containing 60 mg of the drug, taken twice daily.

An effective dose of PTLA is about 10 to 500 mg per kilogram of body weight per day. PTLA is expected to be taken one to four times daily. A preferred regimen is PTLA administered twice daily, comprising oral doses of 75 mg to 450 mg.

The active ingredients mentioned above may be combined in a single composition, or presented as separate preparations. Any pharmaceutically acceptable excipient can be used in the preparation of the pharmaceutical composition containing the two active ingredients, provided the formulation has the required stability and patient acceptability. The most preferred dosage forms are oral solid or liquid dosage forms.

It will be appreciated that the preferred form is to combine the two active ingredients in the same composition for simultaneous administration. However, the active ingredients may also be formulated separately and administered separately so that one active ingredient is used less frequently than the other per day. If the active ingredients are taken separately, it is understandable that they are administered in close proximity, ie one every few minutes. In addition, the doses may vary such that a larger dose of one active ingredient is administered at a certain point in time. For example, taking a larger dose of an active ingredient in the morning is more effective than taking the active ingredient in the evening or making some changes to the regimen. If a compound is taken less frequently per day, the regimen will reduce the dose accordingly. For example, if an antihistamine (eg, loratadine) is to be taken once a day, but PTLA is to be taken twice a day, two or three different dosage forms with special instructions for use will need to be prepared and packaged separately.

These compositions can be tablets, capsules (hard or soft), sweet liquors, syrups, suppositories, etc., which are consistent with conventional pharmaceutical dosage forms for treating cold or flu symptoms. For example, for oral tablets or capsules, the active pharmaceutical ingredient can be mixed with any orally nontoxic pharmaceutically acceptable inert excipients such as lactose, starch, sucrose, cellulose, magnesium stearate, Calcium phosphate, calcium sulfate, mannitol, ethanol (in liquid form), etc. In addition, appropriate binders, lubricants, disintegrants, and colorants can also be used in the mixture when necessary. Suitable binders include starch, gelatin, natural sugars, cereal sweeteners, natural or synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Lubricants that can be used in these dosage forms include boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to: starch, methylcellulose, agar, bentonite, guar gum, and the like. Sweetening and flavoring agents may also be added where appropriate.

Additionally, these compositions can be formulated as sustained release dosage forms to maximize therapeutic efficacy and minimize undesired side effects by controlling the rate of release of one or more ingredients. Suitable sustained release dosage forms include multilayer tablets having layers of different disintegration rates or controlled release polymeric matrices impregnated with active ingredient and tablets or capsules containing such impregnated or encapsulated porous polymeric matrices.

An example of a sustained-release formulation is a partially or completely transparent soft gelatin capsule filled with a pharmaceutically acceptable liquid and small spheres that occupy part of the soft capsule space, or the spheres fill the entire capsule and the spaces between the spheres are filled with the liquid . This dosage form is described in co-pending US applications USSN 08/080815 (filed June 18, 1993) and USSN 08/089361 (filed July 9, 1993), both of which are incorporated herein by reference. The process for making pellets was invented by R.H. Blythe, see US Patent 2,738,303. Therein the process for preparing a therapeutic formulation in unit dosage form from granules without outer walls (sugar pellets) is described: sieved, placed in a coating pan, moistened with syrup, and then treated with an 80:20 mixture of D-amphetamine sulfate and sulfuric acid. The calcium dihydrogen mixture is treated and then dried. This process is repeated several times to make the drug on the granules without outer walls; the treatment with talc gives the sugar pellet cores. These sugar pills are treated one or more times with wax fat coating solution to obtain sugar pills with one or more layers of lipid layers wrapped around the sugar pill core. The dragee core is then surrounded by an osmotic wall through which the drug dissolves in the wall-forming material of the granule and passes through it to the outside world where it comes into contact with water. A reference to such particles is found in US Patent 4,434,153; relevant portions thereof are hereby incorporated by reference. Reference is also made to US Patent No. 4,961,932, which claims pellets and dosage forms containing them.

These dosage forms may be presented as troches, dragees and the like, in which the active ingredient is dissolved or suspended in a base, or in the form of pellets. These formulations may be opaque or translucent or transparent. A preferred dosage form is that of pellets encapsulated in a material forming a solid matrix.

In another example, the pellets can be filled into hard shell gelatin capsules.

Representative examples of dosage forms described in the preceding two paragraphs are described in co-pending US Patent Serial No. 08/090387, filed July 12, 1993, the contents of which are incorporated herein by reference.

Claims (3)

1. one kind is used for the treatment of mammal is reacted the disease that causes by the I para-immunity method, this method comprises a certain amount of peptide leukotriene antagonist and a certain amount of hydryllin of experimenter that is about to suffer from or suffered from described disease, and wherein the two coupling is enough to treat this disease.

2. peptide leukotriene antagonist and hydryllin are used for the treatment of purposes in the medicine of mammal I para-immunity reaction in preparation.

3. one kind is used for the treatment of the Pharmaceutical composition that mammal I para-immunity reacts, and comprises peptide leukotriene antagonist and hydryllin and a kind of pharmaceutically acceptable excipient of effective dose.